The L-two cohomology of Artin groups

For each Artin group we compute the reduced ℓ2-cohomology of its 'Salvetti complex'. This is a CW-complex which is conjectured to be a model for the classifying space of the Artin group. When this conjecture is known to hold our calculation describes the ℓ2-cohomology of the Artin group

CHD4 and the NuRD complex directly control cardiac sarcomere formation

Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type-specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of noncardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the nucleosome remodeling and deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified unique CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal, and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development

The Physics of turbulent and dynamically unstable Herbig-Haro jets

The overall properties of the Herbig-Haro objects such as centerline velocity, transversal profile of velocity, flow of mass and energy are explained adopting two models for the turbulent jet. The complex shapes of the Herbig-Haro objects, such as the arc in HH34 can be explained introducing the combination of different kinematic effects such as velocity behavior along the main direction of the jet and the velocity of the star in the interstellar medium. The behavior of the intensity or brightness of the line of emission is explored in three different cases : transversal 1D cut, longitudinal 1D cut and 2D map. An analytical explanation for the enhancement in intensity or brightness such as usually modeled by the bow shock is given by a careful analysis of the geometrical properties of the torus.Comment: 17 pages, 10 figures. Accepted for publication in Astrophysics & Spac

Cavitation Enhancement Increases the Efficiency and Consistency of Chromatin Fragmentation from Fixed Cells for Downstream Quantitative Applications

One of the most sensitive, time-consuming, and variable steps of chromatin immunoprecipitation (ChIP) is chromatin sonication. Traditionally, this process can take hours to properly sonicate enough chromatin for multiple ChIP assays. Further, the length of sheared DNA is often inconsistent. In order to faithfully measure chemical and structural changes at the chromatin level, sonication needs to be reliable. Thus, chromatin fragmentation by sonication represents a significant bottleneck to downstream quantitative analysis. To improve the consistency and efficiency of chromatin sonication, we developed and tested a cavitation enhancing reagent based on sonically active nanodroplets. Here, we show that nanodroplets increase sonication efficiency by 16-fold and provide more consistent levels of chromatin fragmentation. Using the previously characterized chromatin in vivo assay (CiA) platform, we generated two distinct chromatin states in order to test nanodroplet-assisted sonication sensitivity in measuring post-translational chromatin marks. By comparing euchromatin to chemically induced heterochromatin at the same CiA:Oct4 locus, we quantitatively measure the capability of our new sonication technique to resolve differences in chromatin structure. We confirm that nanodroplet-assisted sonication results are indistinguishable from those of samples processed with traditional sonication in downstream applications. While the processing time for each sample was reduced from 38.4 to 2.3 min, DNA fragment distribution sizes were significantly more consistent with a coefficient of variation 2.7 times lower for samples sonicated in the presence of nanodroplets. In conclusion, sonication utilizing the nanodroplet cavitation enhancement reagent drastically reduces the amount of processing time and provides consistently fragmented chromatin of high quality for downstream applications

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer

Background We explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells. Methods GD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated. Results GD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2 low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity. Conclusions GD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting

Grain coarsening behaviour of solution annealed Alloy 625 between 600–800°C

As with all alloys, the grain structure of the nickel-base superalloy 625 has a significant impact on its mechanical properties. Predictability of the grain structure evolution in this material is particularly pertinent because it is prone to inter-metallic precipitate formation both during manufacture and long term or high temperature service. To this end, analysis has been performed on the grain structure of Alloy 625 aged isothermally at temperatures between 600 and 800 °C for times up to 3000 h. Fits made according to the classical Arrhenius equation describing normal grain growth yield an average value for the activation energy of a somewhat inhomogeneous grain structure above 700 °C of 108.3±6.6 kJ mol−1 and 46.6±12.2 kJ mol−1 below 650 °C. Linear extrapolation between 650 and 700 °C produces a significantly higher value of 527.7±23.1 kJ mol−1. This result is ultimately a consequence of a high driving force, solute-impeded grain boundary migration process operating within the alloy. Comparison of the high and low temperature values with the activation energy for volume self-diffusion and grain boundary diffusion identifies the latter as the principle governing mechanism for grain growth in both instances. A decrease in the value of the time exponent (n) at higher temperatures despite a reduction in solute drag is attributable to the Zener pinning imposed by grain boundary M6C and M23C6 particles identified from Transmission Electron Microscopy (TEM) and Energy Dispersive X-ray Spectroscopy (EDXS) analysis. Vickers hardness results show the dominance of intermetallic intragranular precipitates in the governance of the mechanical properties of the material with grain coarsening being accompanied by a significant increase in hardness. Furthermore, the lack of any correlation with grain growth behaviour indicates these phases have no significant effect on the grain evolution of the material

The T2K ND280 Off-Axis Pi-Zero Detector

The Pi-Zero detector (P{\O}D) is one of the subdetectors that makes up the off-axis near detector for the Tokai-to-Kamioka (T2K) long baseline neutrino experiment. The primary goal for the P{\O}D is to measure the relevant cross sections for neutrino interactions that generate pi-zero's, especially the cross section for neutral current pi-zero interactions, which are one of the dominant sources of background to the electron neutrino appearance signal in T2K. The P{\O}D is composed of layers of plastic scintillator alternating with water bags and brass sheets or lead sheets and is one of the first detectors to use Multi-Pixel Photon Counters (MPPCs) on a large scale.Comment: 17 pages, submitted to NIM

SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (aTubK40me3) during mitosis, with aTubK40me3 required for genomic stability. We now show that monoallelic, Setd2-deficient cells retaining H3K36me3, but not aTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (aTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis

Production and Decay of D_1(2420)^0 and D_2^*(2460)^0

We have investigated $D^{+}\pi^{-}$ and $D^{*+}\pi^{-}$ final states and observed the two established $L=1$ charmed mesons, the $D_1(2420)^0$ with mass $2421^{+1+2}_{-2-2}$ MeV/c$^{2}$ and width $20^{+6+3}_{-5-3}$ MeV/c$^{2}$ and the $D_2^*(2460)^0$ with mass $2465 \pm 3 \pm 3$ MeV/c$^{2}$ and width $28^{+8+6}_{-7-6}$ MeV/c$^{2}$. Properties of these final states, including their decay angular distributions and spin-parity assignments, have been studied. We identify these two mesons as the $j_{light}=3/2$ doublet predicted by HQET. We also obtain constraints on {\footnotesize $\Gamma_S/(\Gamma_S + \Gamma_D)$} as a function of the cosine of the relative phase of the two amplitudes in the $D_1(2420)^0$ decay.Comment: 15 pages in REVTEX format. hardcopies with figures can be obtained by sending mail to: [email protected]